This invention relates to novel pharmaceutical compounds, and in particular to substituted polyamines containing at least 2 electron-affinic groups; methods of preparing these compounds; and methods of using these compounds in various pharmaceutical applications such as in treating diseases caused by anaerobic and micro-aerophilic microorganisms and in radiosensitizing hypoxic tumor cells.
In the United States, alone, over a half million patients undergo radiation therapy each year as a part of their battle against cancer. To date, however, radiation therapy has produced only limited success as a cancer treatment. Understandably, therefore, a major effort has been underway for a number of years to develop means to improve the efficacy of such radiotherapy techniques.
It is widely believed that the presence of radioresistant, hypoxic (poorly oxygenated) cells in tumors constitutes a significant factor in causing local failure in conventional cancer radiotherapy. For example, it was reported by Gatenby et al., Int. J. Radiat. Oncol. Biol. Phys. 14: 831-833 (1988), that for head and neck tumors, the hypoxic cell volume is inversely correlated with tumor radiosensitivity. Other reports confirm this conclusion for a variety of types of tumors and suggest that the presence of a concentration of as little as 2-3% hypoxic cells in a tumor may double the radiation dose required for tumor control.
Various solutions have been proposed to overcome the problem of hypoxia, including carrying out radiation treatments in high pressure oxygen chambers and the substitution of "fast neutron" or .pi. meson radiation in place of X-rays. However, these techniques are not wholly satisfactory for a number of reasons, including the great expense and difficulty frequently associated with such procedures.
One promising field of investigation for dealing with radioresistant hypoxic tumor cells has been the use of "radiosensitizing" compounds which selectively increase the sensitivity of hypoxic cells to radiation. This specificity to hypoxic cells is also valuable because a significant percentage of solid tumors are characterized by such cells while most normal tissue is not. Thus, treatment with such compounds serves to enhance the impact of radiation on tumor cells while having little effect on the impact of radiation on healthy cell tissue. A number of heterocyclic, electron-affinic compounds, and in particular, those with oxidized nitrogen moieties, have been successfully used for the purpose of radiosensitizing hypoxic tumor cells. Specifically, the discovery that the nitroimidazoles, metronidazole ("metro") and misonidazole ("miso"), sensitize hypoxic cells to radiation provided initial optimism for a breakthrough solution to the problem of tumor hypoxia. Unfortunately, however, both agents have proven to be highly toxic at therapeutic levels. Thus, it is clear that a need exists for more potent radiosensitizing compounds which can be administered at lower doses to reduce toxic side effects.
In addition to being used to radiosensitize hypoxic tumor cells, metronidazole recently has been documented and used as an effective antibiotic against Helicobacter pylori ("H. pylori ") in many countries. H. pylori, a fastidious, micro-aerophilic spiral Gram-negative organism, is well established as a principal cause of gastritis, and as a major contributing factor in the development of peptic gastroduodenal ulcers, gastric carcinoma, and lymphoma. In the United States, H. pylori is found in few children, but does colonize the stomach linings of about 20 to 50% of the adults and about 90% of the ulcer patients; the incidence of infection increases with age and is correlated with lower socioeconomic status. In the developing world, the colonization rates generally exceed 80% of the population. Serological evidence shows that 25 to 34% of the United Kingdom population and 52% of the population worldwide are infected. The seriousness of colonization by H. pylori in the United States alone is exemplified by the nearly 21,000 deaths per year due to gastric cancer and the 7,000 deaths per year due to gastric and duodenal ulcers. H. pylori also has been found in association with dental plaque and saliva, suggesting that the oral environment may be one of the potential pathways for transmission.
Unfortunately, H. pylori is a relatively difficult infection to treat. The gastric habitat offers sanctuaries beneath the mucous layer and within the lumen of gastric glands and pits that partially shelter H. pylori form the topical or luminal effects of some antibiotics. Gastric acidity inactivates many other antibiotics. Furthermore, H. pylori has shown a propensity to rapidly acquire resistance to many classes of antibiotics after exposure to those agents in the form of monotherapy. These include the fluoroquinolones, the macrolides, the nitroimidazoles (including metronidazole), and rifampin.
Therefore, at the present time, no single H. pylori eradication regimen is generally accepted by clinicians. The most successful treatment has been achieved using triple therapy wherein metronidazole is administered in conjunction with a bismuth compound and either amoxicillin or tetracycline. Many patients, however, are intolerant to such multiple-antibiotic therapy. In fact, up to 50% of patients have reported some degree of intolerance. This medication intolerance will affect compliance, and it has been shown that compliance is an important factor in the success of triple therapy.
Metronidazole also is disadvantageous due to the existence of metronidazole-resistant H. pylori strains. Indeed, the presence of metronidazole-resistant H. pylori has been shown to have a considerable impact on the success of triple therapy. One recent report on 40 patients noted a 90.5% bacterial eradication rate for triple therapy (a 2-week course) against metronidazole-susceptible strains, but only a 31.6% bacterial eradication rate against metronidazole-resistant strains (p&lt;0.01) which accounted for 48% of that study's U.K. population. In another study, Decross et al. similarly reported that dual therapy (i.e., bismuth and metronidazole) proved to be highly effective against metronidazole-susceptible strains (81.6% eradication rate) but fared poorly against resistant strains (16.7% eradication rate; p&lt;0.01). Thus, there is a great need to develop novel electron-affinic compounds which are much more effective in killing H. pylori than metronidazole, can overcome metronidazole resistance, and have reduced side effects.
In addition to the foregoing uses, metronidazole has been used in various other pharmaceutical applications. For example, metronidazole has been reported to be effective for treating viral infections such as measles, herpes, and viral diverticulitis. It also has been reported to be effective in treating cutaneous inflammation due to dermatosis such as eczema, ulcers, acne, and rosacea. Additionally, it has been reported to be effective in treating eye disorders such as blepharoconjunctivitis and meibomian gland dysfunctions.
Despite these many uses, however, metronidazole is disadvantageous because of its toxicity and various side effects. For example, when it is taken internally, it tends to cause nausea and when it is used in high doses (e.g., when it is used as a radiosensitizer), it tends to cause peripheral neuropathy. In addition, it is disfavored because it is a mutagen. Furthermore, since it is a photosensitizer, it is disfavored for dermatological applications.
Thus, a great need ultimately exists for potent metronidazole substitutes which have less toxicity while being more effective in pharmaceutical applications such as radiosensitizing hypoxic tumor cells and treating internal and dermatological diseases such as infectious diseases caused by anaerobic and micro-aerophilic microorganisms.